The Sonic Hedgehog (Shh) signaling pathway is a key mediator of the endogenous response to tissue injury and represents a promising strategy for ischemic tissue repair. Hedgehog Interacting Protein (Hhip) is a cell surface regulator of Shh signaling which has been shown to be highly expressed on endothelial cells. However, its role in adult cardiovascular physiology and in Shh mediated angiogenesis is poorly understood. Therefore, we propose to determine the role of Hedgehog Interacting Protein in Sonic Hedgehog mediated angiogenesis. We hypothesize that Hhip is a major regulator of the effects of Shh on the endothelium and that downregulation of Hhip will enhance Shh mediated angiogenesis. To investigate the role of Hhip in Shh mediated angiogenesis, we propose the following specific aims: Specific Aim #1: Determine the effect of Hhip on Shh signaling and response in endothelial cells Specific Aim #2: Elucidate the regulation of Hedgehog Interacting Protein expression in endothelial cells Specific Aim #3: Determine whether modulation of Hhip can enhance Shh mediated angiogenesis using the Matrigel plug mouse model. At the conclusion of this project, we expect to have determined the role of Hhip in Shh mediated angiogenesis and whether modulation of Hhip represents a promising step forward toward a new treatment strategy for ischemic cardiovascular diseases. The long-term goal of our investigations is to leverage basic insights about pathophysiology and endogenous repair mechanisms to develop a biological treatment for chronic ischemic diseases. If our hypothesis is correct, modulation of Hhip could represent a novel approach for biological ischemic tissue repair. Public Health Relevance: cardiovascular diseases are the number one cause of morbidity and mortality in the United States and are an immense global health issue. Promising strategies to repair areas of the body (for example: heart, brain, lower limbs) that suffer from inadequate blood supply are desperately needed. This project will determine whether targeting a component of the Sonic Hedgehog pathway can enhance the natural healing response mediated by this pathway and the mechanisms for this effect.